Scientists reveal mechanism behind high-fat, diabetes link

New research explains the mechanism behind the widely recognized link between a high-fat diet and type 2 diabetes, providing an insight into how high-fat diet-induced diabetes may be prevented.

The study, published last week in the journal Cell, identifies a molecular link between the consumption of fatty foods and the disruption of insulin production.

According to scientists at the University of California, San Diego (UCSD) School of Medicine, a single gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a) is key to enabling the beta cells in the pancreas to sense blood glucose levels and appropriately produce insulin.

However, this enzyme is suppressed by a high-fat diet, resulting in pancreatic beta cell failure and eventually leading to type 2 diabetes.

The researchers found that mice lacking the GnT-4a gene had elevated blood glucose concentrations- the first measure of diabetes. The consequent failure of beta cells to normally secrete insulin resulted in the development of the disease.

The numbers of consumers with diabetes are rising the world over, linked to lifestyle factors such as diet, exercise and weight, all established risk factors for type 2 diabetes.

An estimated 41 million Americans have 'pre-diabetes', or impaired glucose tolerance, in which blood sugar levels are higher than normal and lead to high risk of developing type 2 diabetes.

And around 25 per cent of UK adults are also believed to have this condition: the number of people with diabetes, now 3 per cent of the population, will continue to rise as the population ages and becomes increasingly overweight.

According to the latest research, the key role of the GnT-4a enzyme is to maintain glucose transporters on the surface of the beta cells in the pancreas. Pancreatic glucose transporters are necessary at the beta cell surface to sense glucose levels in the blood.

When glucose is elevated after a meal, the transport of glucose by these transporters triggers the beta cell to secrete insulin. Proper insulin secretion is essential to enable the rest of the body to metabolize glucose and convert it to cellular energy, explained the scientists.

"Our findings suggest that the current human epidemic in type 2 diabetes may be a result of GnT-4a enzyme deficiency," said Dr Jamey Marth, UCSD professor of cellular and molecular medicine.

"The GnT-4a enzyme is required to synthesize a glycan structure that holds the glucose transporter in place at the beta cell surface. The loss of this key transporter is directly linked to reduced GnT-4a protein glycosylation, a high-fat diet, and type 2 diabetes," he added.

According to Marth and his colleagues, their latest findings could lead to a new approach to the prevention of diabetes resulting from a high-fat diet.

Variations in susceptibility to type 2 diabetes may result from inherited differences in the gene for GnT-4a that may ultimately affect its level or activity, they said.

"If you could somehow stimulate production of this enzyme, you might be able to render animals, and perhaps humans, resistant to high-fat diet-induced diabetes," said Marth.

To test the theory, the scientists are currently conducting experiments on mice in order to determine whether the over-expression of the GnT-4a gene makes them resistant to diabetes induced by a high-fat diet.

"While a deficiency of insulin can cause diabetes, too much insulin can also be harmful, and has been found to contribute to the pathogenesis of cancer, cardiovascular disease, ovarian diseases, and Alzheimer's disease," said the scientists.

"It may be that suppressing insulin production to some degree could be beneficial in such disorders, and that could theoretically be achieved by inhibiting the GnT-4a glycosyltransferase," added Marth.

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